Molecular Profile of Intrahepatic Cholangiocarcinoma

Abstract

Intrahepatic cholangiocarcinoma (ICC) is a relatively uncommon but highly aggressive primary liver cancer that originates within the liver. The aim of this study is to review the molecular profile of intrahepatic cholangiocarcinoma and its implications for prognostication and decision-making. This comprehensive characterization of ICC tumors sheds light on the disease's underlying biology and offers a foundation for more personalized treatment strategies. This is a narrative review of the prognostic and therapeutic role of the molecular profile of ICC. Knowing the molecular profile of tumors helps determine prognosis and support certain target therapies. The molecular panel in ICC helps to select patients for specific therapies, predict treatment responses, and monitor treatment responses. Precision medicine in ICC can promote improvement in prognosis and reduce unnecessary toxicity and might have a significant role in the management of ICC in the following years. The main mutations in ICC are in tumor protein p53 (TP53), Kirsten rat sarcoma virus (KRAS), isocitrate dehydrogenase 1 (IDH1), and AT-rich interactive domain-containing protein 1A (ARID1A). The rate of mutations varies significantly for each population. Targeting TP53 and KRAS is challenging due to the natural characteristics of these genes. Different stages of clinical studies have shown encouraging results with inhibitors of mutated IDH1 and target therapy for ARID1A downstream effectors. Fibroblast growth factor receptor 2 (FGFR2) fusions are an important target in patients with ICC. Immune checkpoint blockade can be applied to a small percentage of ICC patients. Molecular profiling in ICC represents a groundbreaking approach to understanding and managing this complex liver cancer. As our comprehension of ICC's molecular intricacies continues to expand, so does the potential for offering patients more precise and effective treatments. The integration of molecular profiling into clinical practice signifies the dawn of a new era in ICC care, emphasizing personalized medicine in the ongoing battle against this malignancy.

Keywords: cholangiocarcinoma; liver neoplasms; tumor biomarkers.

Figure 1

Isocitrate dehydrogenase (IDH) is an enzyme that plays a critical role in cellular metabolism, specifically in the tricarboxylic acid cycle. IDH catalyzes the conversion of isocitrate into alpha-ketoglutarate. IDH mutations promote the accumulation of 2-hydroxyglutarate, preventing the demethylation of DNA and histones and promoting cancer initiation.

Figure 2

In its normal state, the Kirsten rat sarcoma virus (KRAS) protein acts as a molecular switch, cycling between active (GTP-bound) and inactive (GDP-bound) forms to transmit signals for cell survival and proliferation in response to external growth signals. Activated KRAS protein can act on the RAF-MEK-ERK and the PI3K-AKT-mTOR pathways, which regulate cell proliferation, differentiation, migration, and inhibition of apoptosis.

Figure 3

AT-rich interaction domain 1A (ARID1A) is a part of the SWI/SNF chromatin remodeling complex. ARID1A inhibits the PI3K/AKT and JAK/STAT pathways, limiting cell survival and proliferation capability. Additionally, ARID1A promotes DNA repair, avoiding the accumulation of mutations. Dotting lines represent inhibition while solid lines represent stimulation.